Nucleic acid aptamers are in vitro evolved nucleic acids that are able to bind and inhibit protein function.
Nucleic acid aptamers have been developed over the last 20 years to develop therapeutic aptamers against a variety of targets for a number of diseases including macular degeneration, HIV, cancer, cardiovascular disease, amongst others. One aptamer, pegaptanib (MACUGEN), is used clinically for the treatment of macular degeneration, discovered by Gilead Sciences, licensed to Eyetech Pharmaceuticals and marketed outside the USA by Pfizer. Other aptamer based drugs are in clinical trials against coagulation factors, growth factors, inflammation markers and other targets. To our knowledge, no aptamers have been developed in relation to osteoporosis.
Osteoporosis has a significant medical and economic impact worldwide. In developed nations, approximately 4% of the population has osteoporosis, and the economic burden to the US alone has been estimated at $14 billion annually. Currently, the majority of pharmacological agents presently used in the clinic are bisphosphonate based antiresorptive agents, including alendronate (FOSAMAX), risedronate (ACTONEL) or ibandronate (BONIVA).
The established drug agents can be somewhat effective in controlling bone mass, but they have a number of disadvantages including poor oral absorption, esophagitis and osteonecrosis of the jaw. Therefore, there is a move toward anabolic agents that stimulate bone formation that would potentially accelerate bone growth. Recently, teriparatide (recombinant parathyroid hormone, FORTEO) was approved as the first anabolic agent to enter the clinic but there have been some concerns regarding FORTEO that it is only effective to remodel bone during the first 12 months treatment and then efficacy declines.
Sclerostin is an osteocyte-specific negative regulator of bone formation which makes it an attractive drug target for osteoporosis therapy. Amgen is developing protein-based antibodies against sclerostin for osteoporosis therapy (Human Clinical Phase 2). Novartis and Eli Lily are also developing sclerostin-blocking antibodies (Preclinical). OsteogeneX is developing small molecule inhibitors against sclerostin, currently in preclinical and lead optimization.
Antibodies generally have a number of limitations including risk of immune response, batch to batch variation and limited shelf-life. Small molecules have significant problems of binding affinity and specificity.